Inhibition of DPP-IV, an enzyme that inactivates both glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), represents a novel approach to the treatment and prevention of type 2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM). The therapeutic potential of DPP-IV inhibitors for the treatment of type 2 diabetes has been reviewed: C. F. Deacon and J. J. Holst, “Dipeptidyl peptidase IV inhibition as an approach to the treatment and prevention of type 2 diabetes: a historical perspective,” Biochem. Biophys. Res. Commun., 294: 1-4 (2000); K. Augustyns, et al., “Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of type 2 diabetes,” Expert. Opin. Ther. Patents, 13: 499-510 (2003); and D. J. Drucker, “Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of Type 2 diabetes,” Expert Opin. Investig. Drugs, 12: 87-100 (2003).
WO2003/004498, assigned to Merck Sharp & Dohme Corp., describes a class of beta-amino tetrahydrotriazolo[4,3-a]pyrazines, which are potent inhibitors of DPP-IV, and therefore are useful for the treatment of type 2 diabetes. Specifically disclosed in WO 03/004498 is 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine. While pharmaceutically acceptable salts of this compound are generically encompassed within the scope of WO 03/004498, there is no specific disclosure the sitagliptin tannate complex.
WO2005/003135, also to Merck Sharp & Dohme Corp., discloses the dihydrogenphosphate salt of sitagliptin. The publication indicates that the dihydrogenphosphonate salt is a potent inhibitor of DPP-IV and, therefore, is useful for the treatment and prevention of non-insulin dependent diabetes mellitus, also referred to as type 2 diabetes, obesity and high blood pressure. WO2005/003135 also describes a crystalline monohydrate of the dihydrogenphosphate salt as well as a process for its preparation, pharmaceutical compositions containing this novel salt form, and methods of use for the treatment of type 2 diabetes, obesity, and high blood pressure. WO2005/003135 does not describe a sitagliptin tannate complex. WO2005/072530, WO2006/033848, and WO2007/035198, all to Merck Sharp & Dohme Corp., describe salts of sitagliptin.
Tannic acid, also known as tannin, gallotannin, glycerite or gallotannin, is a yellowish to light brown amorphous powder having the approximate composition of C76H52O46 and a molecular weight of about 1701 grams/mol. Although tannic acid is typically produced from Turkish or Chinese nutgall, it can be derived from the bark and fruit of many plants. Tannic acid is very soluble in water, glycerin or alcohol. Tannic acid may be obtained either by extraction from natural products or through synthetic chemical synthesis.
Tannate complexes comprising pharmaceutically active compounds are known in the art. See, e.g., U.S. Pat. No. 5,663,415; U.S. Pat. No. 6,881,741 B2; U.S. Pat. No. 6,939,856 B2; U.S. Pat. No. 6,670,370 B1; and U.S. Pat. No. 7,547,806 B2. Tannate salts have been found to have better organoleptic properties, such as taste, in comparison to other salts or free base forms. See, e.g., US 2005/0202050 A1 or US 2003/0083354 A1. Additionally, Vummaneni et al. (International Journal of Research in Pharmaceutical and Biomedical Sciences 3(2), 510-524 (2012)) report that tannic acid acts as a taste masker for chloroquine phosphate. Moreover, as tannate salts are relatively large molecules, they afford absorption of the pharmaceutically active compound over a prolonged period of time and hence can be used in sustained release preparations. See, e.g., U.S. Pat. No. 7,547,806 B2; US 2005/0202050 A1 or US 2003/0083354 A1.
Sitagliptin as a monohydrate phosphate salt is the active ingredient in JANUVIA® and one of the active agents in JANUMET® AND JANUMET XR®, all marketed by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., to improve glycemic control in adults with type 2 diabetes mellitus. An unintended effect of sitagliptin monohydrate phosphate is that it has an intense, lingering bitter taste. In order to overcome this bitter taste, drug products containing sitagliptin monohydrate phosphate are formulated as a film-coated tablet. Marketing sitagliptin monohydrate phosphate as a film-coated tablet is not always ideal as an estimated 20% of the patients taking JANUMET® experience a difficulty in swallowing the tablet.
Hence, there is a need to develop alternative intra-oral dosage forms with a pleasant taste for patient populations (e.g., the elderly or children) who cannot swallow the large tablets. Moreover, any of these alternative intra-oral dosage forms must be relatively easy to manufacture to make the product cost effective. This and other objectives will become evident from the following description.